1. Technical Field
This invention relates to a method for treating severe chronic inflammatory disease, such as demyeliniating diseases, uveitis, or graft-versus-host disease, by administrating tumor necrosis factor or "TNF" in an effective antisevere chronic inflammatory disease amount to a patient suffering from the disease.
2. Background Art
Severe chronic inflammatory disease is a generic name of a category of diseases which have no fundamental remedy because the mechanism of incidence has not been elucidated and is characterized by its regional and generalized chronic inflammatory symptoms. Severe chronic inflammatory disease consists of demyelinating disease, uveitis, graft-versus-host disease and the like.
The main morbific cause of demyelinating disease is a destruction of the myelin sheath of a nerve or nerves. It is generally classified into multiple sclerosis and acute disseminated encephalomyelitis. Demyelinating disease also includes disseminated sclerosis, leukodystrophy and the like. It has been considered that allergic reactions to the myelin sheath are related to the incidence of demyelinating disease. However, the cause of these reactions has not yet been elucidated. Multiple sclerosis is different from acute disseminated encephalomyelitis and other demyelinating diseases, because multiple sclerosis is characterized by remissions and persistently recurring exacerbations. Acute disseminated encephalomyelitis can be transformed into multiple sclerosis.
The presenting symptoms of demyelinating disease are neurologic disorders which mainly consist of ataxia and paresthesias. Demyelinating disease is sometimes fatal in the acute period. In spite of such severity, no efficient therapeutic method exists. As therapeutic methods for multiple sclerosis, adrenocortical hormone-like agents are used for the exacerbation period. For the remission period medical rehabilitation and medical preventive treatment against infection are utilized. But, demyelinating disease cannot be healed by these treatments. As therapeutic methods for acute disseminated encephalomyelitis, the use of adrenocortical hormone-like agents are effective in some cases. However, after the treatment, some problems remain such as neurologic disorders and transference into multiple sclerosis.
Uveitis is an inflammation of the eye which is caused by various diseases as an original disease, such as Behcet's disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis or toxoplasmosis. The symptoms of anterior uveitis are iridocyclitis and hypopyon. The symptoms of posterior uveitis are opacity of the vitreousbody, hemorrhage and extravasation on the eyeground, edema and opacification on the retina and neuritis optica. Posterior uveitis leads to a reduction or a loss of visual activity through complicated cataract or glaucoma. The mechanism of incidence of uveitis and the relation to the original diseases have not been elucidated. Neither have the cause or causes of Behcet's disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis or toxoplasmosis been elucidated.
As therapeutic methods for uveitis, the instillation of mydriatic agents and steroidal agents and the general administration of steroidal agents have been conventionally utilized. The use of steroidal agents and immunosuppressive agents for a long-term administration has been utilized with the aim of prophylaxis and mitigation of uveitis, because uveitis is often recurs and tends to be chronic. However, steroidal agents and immunosuppressive agents such as cyclosporine are known for their strong side effects, and it is known that long-term administration can be life-threatening. Moreover, the effects of these agents have not been justified. The reduction in the dose and the interruption of the administration in cases where there is no improvement often causes the disease to become chronic.
Graft-versus-host disease (hereinafter "GVHD") is often observed in patients with foreign bone marrow transplantations. The major symptoms are fever, lesion, diarrhea and liver disorders. GVHD is a life-threatening disease. The bone marrow transplantation is performed on patients who are deficient in or lack hematopoietic stem cells and immunity-charging cells in cases such as aplastic anemia, severe immune difficiency and leukemia. It is also performed on patients whose myelopoietic function has been destroyed by radiation therapy and chemotherapy. However, there are many problems to be solved in the use of bone marrow transplantation, including the occurrence of such disorders as GVHD, interstitial pneumonia, reoccurrence and infection. GVHD sometimes causes interstitial pneumonia. The ratio of incidence of GVHD is very high when the bone marrow transplantation is utilized, making GVHD one of the major obstacles to bone marrow transplantation.
GVHD is classified into acute GVHD and chronic GVHD depending on the onset of GVHD. Also, there are differences between acute GVHD and chronic GVHD in clinical aspects. Acute GVHD occurs within 100 days after grafting. The main targets of acute GVHD are the skin, the liver and the gastrointestinal tract. The clinical symptoms of acute GVHD are erythema, bulla and erosion on the skin, icterus and diarrhea which are caused by the disorders of the organs mentioned above. Chronic GVHD occurs after 100 days following grafting. The targets of chronic GVHD are wider than those of acute GVHD. Therefore, the symptoms of chronic GVHD take various forms. Chronic GVHD is classified into localized GVHD and generalized GVHD according to the clinical findings. The main symptom of localized GVHD are lesions which include drying, lichen planus-like change, pigmentation, depigmentation and erythema accompanied with detachment. It sometimes accompanies with liver disorders. The syndrome of generalized GVHD consists of affections of the mucous membrane of the salivary gland, the mouth and the esophagus, the iachrymals, the lung, the bronchus, muscle and the joint. These symptoms lead to a reversion of autoantibodies and are similar to the symptoms of autoimmune disease.
As therapeutic methods for GVHD, general administration of immunosuppressive agents, such as methotrexate, steroids, azathioprine and cyclosporine A has been conventionally utilized. However, they have problems with side effects which have yet to be solved.
Tumor necrosis factor, or "TNF", was discovered originally in mouse serum after intravenous injection of bacterial endotoxin into mice primed with viable Mycobacterium bovis, strain Bacillus Calmette-Guerin (BCG). See, Proc. Nat. Acad. Sci. U.S.A., 72(9), 3666-70 (1975). TNF-containing serum from mice is cytotoxic or cytostatic to a number of mouse and human transformed cell lines, but less so to normal cells in vitro. It causes necrosis of transplantable tumors in mice. TNF also occurs in the sera of the rat, rabbit and guinea pig. Further, it is also known that TNF can be produced by mononuclear phagocytes, fibroblasts, B-cells, and the like derived from a mammal under certain conditions. In this connection, there are many reports in the literature which have been summarized by Lloyd J. Old in Scientific American, 258(5), 59-75 May, 1988).
TNF is now being developed under clinical trials for use as an anti-tumor agent. It is also reported that TNF has an anti-inflammatory effect and an anodzne effect [Japanese Patent Application laid-open No. 62-292727]. It is also reported that TNF has a suppressive effect against autoimmune disease defined as immune complex-disease [European Patent 254647] and a therapeutic effect against inflammatory skin disease such as atopic dermatitis [WO 90/05532]. However, there is no disclosure that TNF is effective against severe chronic inflammatory disease, such as demyelinating disease, uveitis, or graft-versus-host disease. On the contrary, it is reported that TNF may be one of the substances related to the destruction of the myelin sheath in demyelinating disease [Hofman et al., J. Exp. Med. 170, 607-612 (1989)]. It is also reported that an intravitreous administration of TNF causes an inflammatory reaction in the anterior eye [Rosembaum et al., Am. J. Pathol. 133. 47-53 (1988)]. It is also reported that TNF may be one of the substances related to skin and gastrointestinal tract disorders in acute GVHD [Piguet et al., J. Exp. Med. 166, 1280-1289 (1987)].
Considering the description of the above-mentioned reports, it was expected that TNF would not be useful for the purpose of treating demyelinating disease, uveitis, or graft-versus-host disease.
However, unexpectedly, our experimental data, i.e. in vivo data and data on the different condition of the dosage from those in the above-mentioned reports, show that TNF would be useful for the purpose of treating demyelinating disease, uveitis, or graft-versus-host disease.
Based on these novel findings, the present invention has been completed.
Accordingly, it is an object of the present invention to provide a novel therapeutic method effective for treating demyelinating disease.
Another object is to provide a novel therapeutic method effective for treating uveitis.
Another object is to provide a novel therapeutic method effective for treating graft-versus-host disease.
These and other objects of the invention as well as the advantages thereof can be had by reference to the following description and claims.